Immunotherapy resistance pathways investigated to tailor combination NSCLC therapy
Prof Pascale Tomasini - Aix-Marseille University, Marseille, France
In the ESMO congress I presented the results of the PIONeeR trial which is a phase Ib/IIa clinical trial designed to overcome resistance pathways to PD-1 and PD-L1 inhibitors in advanced non-small cell lung cancer. This trial is part of a large programme aimed to study and overcome resistance to PD-1 and PD-L1 inhibitors in non-small cell lung cancer with a biomarker programme and then a clinical trial programme.
This clinical trial programme results from an academic network of clinicians and researchers. We enrolled patients with advanced non-small cell lung cancer, ECOG 0 or 1, who had disease progression after PD-1 or PD-L1 inhibitors. The patients were randomised between different combination arms with durvalumab, one arm with the NKG2A inhibitor monalizumab, another one with oleclumab, the CD73 inhibitor oleclumab, another arm with the ATR inhibitor ceralasertib and another arm with the Met inhibitor savolitinib. All these experimental arms were compared to the standard chemotherapy docetaxel.
The primary endpoint was the 12-week disease control rate. In this trial we used an innovative and adaptive design with a Bayesian approach where we could during the trial stop quickly arms with no signal of efficacy or, on the contrary, add new arms when new data emerged with promising new combinations or molecules.
We enrolled 114 patients in the trial. Two arms were stopped prematurely, the arm with oleclumab was stopped after only 3 patients because of no efficacy signal reported in a concurrent trial. The savolitinib arm was stopped because of futility shown in the first interim analysis of our trial. Finally, no experimental arm succeeded in meeting the Bayesian criteria of efficacy in comparison with docetaxel regarding the primary endpoint, 12-week disease control rate, but also the secondary endpoints with response and survival.
However, when considering individual outcome data we saw that some patients in the experimental arms with monalizumab and ceralasertib derived some durable clinical benefit from the combinations with significant responses in the target lesions and with long-term clinical benefit of more than one year. When considering the standard clinical and biological data of all these patients with durable clinical benefit we could not see any similarity and there is a real need to go further with biomarker analysis in order to be able to identify these patients. These biomarker analyses are ongoing.
The safety profile was as expected, maybe with the exception of the ceralasertib arm where we had to adjust the dosing schedule of ceralasertib in order to ensure a better safety and efficacy profile. Especially for safety, for the haematologic toxicity.
So, to conclude, the PIONeeR trial is an academic collaborative success with an innovative and adaptive design with a Bayesian approach which is quite original. We were able with this approach to experiment several combination arms in comparison with docetaxel. Whereas no experimental arm met the efficacy criteria in comparison with docetaxel, we saw that some patients had long-term clinical benefit, especially from monalizumab and ceralasertib combinations and biomarker analyses are ongoing in order to be able to identify these patients.
